Small Molecules

An Overview of Emerging Therapeutic Options in the Treatment of Psoriasis

Melinda Gooderham, MD, MSc, FRCPC

Disclosures

Skin Therapy Letter. 2013;18(7) 

In This Article

JAK Inhibitors (Jakinibs)

Introduction

The Janus kinases, a group of tyrosine kinases comprised of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), are mainly found in hematopoietic cells. These kinases reside on the cytoplasmic side of Type I and II cytokine receptors. Kinases are invoked as part of signal transmission when cytokines bind to their cognate receptors. JAKs activate the intracellular transcription factors known as signal transducers and activators of transcription (STATs). The binding of STAT to an activated JAK results in phosphorylation and subsequent dimerization and translocation to the nucleus, where it directly modulates gene transcription.[1–3]

The JAKs play an important role in immune defense as we have learned from a series of mutant cell lines, mouse knock-out models and the clinical expression of JAK3 mutations, resulting in severe combined immunodeficiency. Inhibiting this pathway has been beneficial in treating immune-mediated diseases, including rheumatoid arthritis, inflammatory bowel disease and psoriasis, as well as preventing allograft rejection.[3]

The JAK inhibitors, or so-called jakinibs, uncouple cytokine receptor signaling from downstream STAT transcription activation and, thereby, modulate immune response in these disease states (Figure 1). The potential side effects of these agents are partially predictable and are directly related to their mode of action. These effects can include neutropenia and anemia, which are likely related to JAK2 inhibition. JAK2 is associated with the erythropoietin (EPO) receptor. Such effects are possibly doserelated and, to date, have been mild and appear not to be limiting usage. Not as well understood are some reports of hyperlipidemia (total cholesterol, LDL cholesterol and HDL cholesterol) similar to that seen with the interleukin (IL)-6 inhibitor, tocilizumab.[3] This mechanism is still under investigation.

Figure 1.

JAK inhibitors uncouple cytokine receptor signaling from downstream STAT transcription activation and thereby modulate immune response
STAT = signal transducers and activators of transcription; P = phosphate

Tofacitinib

One of the first JAK inhibitors used in humans was tofacitinib (formerly called tasocitinib), a potent inhibitor of JAK3, which was also found to have activity against JAK1 and to a lesser extent JAK2.[1,3] It has been reported to be a safe and effective therapy for ulcerative colitis[4] and rheumatoid arthritis, both with and without concomitant methotrexate therapy.[5,6] Tofacitinib has been approved for use in rheumatoid arthritis in the US. For psoriasis, the initial Phase 1 trial was a randomized, doubleblind, placebo-controlled, dose-escalation study examining 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg twice daily (BID) and 60 mg once daily (OD) for 14 days in 59 patients.[7] Boy et al. (2009) found a significant dose-dependent decrease in erythema, induration and scaling using the Psoriatic Lesion Severity Sum (PLSS) from baseline to day 14 in all doses except 5 mg BID.[7] Results of skin biopsies showed marked histological improvement at the higher dose of 30 mg BID with decrease in lesional thickness and K16 expression (a keratinocyte growth activation marker) to normal or near normal.[7] In this initial study, adverse effects noted were an increase in total cholesterol, LDL cholesterol and triglyceride compared to placebo.

Papp et al. (2012) published results of the Phase 2b dose-ranging study in psoriasis.[8] One hundred and ninety-seven patients with severe psoriasis were randomized to receive tofacitinib 2 mg, 5 mg, 15 mg or placebo BID and a clear dose-response was observed. A significant Psoriasis Area and Severity Index (PASI) 75 response was seen as early as week 4 and lasted through week 12. They reported a PASI 75 of 25% (2 mg, p<0.001), 40.8% (5 mg, p<0.0001) and 66.7% (15 mg, p<0.0001) in treated patients vs. 2% of patients in the placebo group.[8] Patients treated with tofacitinib also demonstrated a significant and rapid improvement in pruritus compared to those receiving placebo.[9]

The most common adverse effect reported was infection and some dose-related changes in laboratory parameters were also observed. Mild reductions in hemoglobin and mean absolute neutrophil counts were noted starting at week 2 and were most pronounced in the 15 mg BID group; elevations in total cholesterol, HDL cholesterol and LDL cholesterol were also reported in a dose-related fashion similar to Phase 1 data.[8] Currently, Phase 3 studies are evaluating the safety and efficacy of 5 mg and 10 mg BID dosing; as well, one comparator study is being conducted with etanercept.

As of October 2013, Pfizer announced that two of the five psoriasis Phase 3 studies have reported beneficial results as expected from Phase 2 data.[10] The 12-week non-inferiority study comparing tofacitinib with high-dose etanercept and the 56-week retreatment investigation both met primary safety and efficacy endpoints, and further information should be published in the coming months.

Baricitinib

A newer JAK inhibitor under investigation is baricitinib (Eli Lilly), which preferentially inhibits JAK2 over JAK1 and JAK3. Not much has yet been published on this molecule and it has just recently completed Phase 2 trials. The Phase 2b study was a randomized, double-blind, dose-escalation study evaluating 2 mg, 4 mg, 8 mg, and 10 mg BID vs. placebo (ClinicalTrials.gov, identifier NCT01490632). Phase 1 and 2 data have not yet been published.

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